The objective of the proposal is to determine optimal dose schedules against murine leukemia for certain purine and pyrimidine nucleoside analogues from an experimental knowledge of the differential biochemical and pharmacological effects of these compounds on tumor and host tissues. Compounds to be investigated include: arabinosyladenine, arabinosyl-2-fluoroadenine, 3-deazauridine, arabinosylcytoside, xylosyladenine and 2'-deoxyribosyl-2-choloradenine. The accumulation and flux of the active triphosphate forms of these compounds will be determined by high-pressure liquid chromatographic procedures, and will be compared with their effects on cellular macromolecular synthesis, incorporation into nucleic acids and alterations in the levels of normal cellular metabolites. Drug-induced differences in these parameters in tumor and host tissues that are suggestive of a chemotherapeutically exploitable basis for increasing the therapeutic index by dose scheduling will be tested. Parallel studies, using mammalian cells in culture, in which drug toxicity is readily quantitated and of the biochemical basis for the observed toxicity is facilitated, will be carried out. The procedures established by these studies may be generally applicable to the rational determination of dose schedules to a variety of drugs under development and the methodology employed should be useful in monitoring chemotherapy protocols in clinical trials.